JP6505235B2 - リポソームを用いるアミロイド斑のmriイメージング - Google Patents
リポソームを用いるアミロイド斑のmriイメージング Download PDFInfo
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- JP6505235B2 JP6505235B2 JP2017538918A JP2017538918A JP6505235B2 JP 6505235 B2 JP6505235 B2 JP 6505235B2 JP 2017538918 A JP2017538918 A JP 2017538918A JP 2017538918 A JP2017538918 A JP 2017538918A JP 6505235 B2 JP6505235 B2 JP 6505235B2
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- Prior art keywords
- phospholipid
- polymer
- aromatic
- liposome composition
- substituted
- Prior art date
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- 239000002502 liposome Substances 0.000 title claims description 118
- 208000037259 Amyloid Plaque Diseases 0.000 title claims description 66
- 238000003384 imaging method Methods 0.000 title claims description 23
- 239000000203 mixture Substances 0.000 claims description 86
- 125000003118 aryl group Chemical group 0.000 claims description 69
- 239000002245 particle Substances 0.000 claims description 54
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- 238000002595 magnetic resonance imaging Methods 0.000 claims description 35
- 229920000642 polymer Polymers 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 150000003904 phospholipids Chemical class 0.000 claims description 25
- 238000001514 detection method Methods 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
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- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 11
- 125000005647 linker group Chemical group 0.000 claims description 11
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 8
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- 238000004458 analytical method Methods 0.000 claims description 6
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 4
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- LYRFLYHAGKPMFH-UHFFFAOYSA-N octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(N)=O LYRFLYHAGKPMFH-UHFFFAOYSA-N 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 3
- 150000000921 Gadolinium Chemical class 0.000 claims 2
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 150000002431 hydrogen Chemical class 0.000 description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
- 125000002950 monocyclic group Chemical group 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 229910052736 halogen Inorganic materials 0.000 description 20
- 150000002367 halogens Chemical class 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical group [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 18
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
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- 238000005481 NMR spectroscopy Methods 0.000 description 15
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- 125000001424 substituent group Chemical group 0.000 description 15
- XFFSCOOTVXBLCK-QAVVBOBSSA-N OC(=O)c1cc(ccc1O)\N=N\c1ccc(cc1)-c1ccc(cc1)\N=N\c1ccc(O)c(c1)C(O)=O Chemical compound OC(=O)c1cc(ccc1O)\N=N\c1ccc(cc1)-c1ccc(cc1)\N=N\c1ccc(O)c(c1)C(O)=O XFFSCOOTVXBLCK-QAVVBOBSSA-N 0.000 description 14
- 239000013522 chelant Substances 0.000 description 13
- 230000000875 corresponding effect Effects 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- MVJKUWANBPLVFJ-GORDUTHDSA-N 2-[N-methyl-4-[(E)-2-pyrimidin-4-ylethenyl]anilino]ethanol Chemical compound CN(CCO)C1=CC=C(C=C1)\C=C\C1=NC=NC=C1 MVJKUWANBPLVFJ-GORDUTHDSA-N 0.000 description 11
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 10
- CBRMVHHBOZCVFN-DUXPYHPUSA-N 2-methoxy-4-[(E)-2-pyrimidin-4-ylethenyl]phenol Chemical compound COC1=C(C=CC(=C1)\C=C\C1=NC=NC=C1)O CBRMVHHBOZCVFN-DUXPYHPUSA-N 0.000 description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 9
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000013595 glycosylation Effects 0.000 description 8
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- 229920000233 poly(alkylene oxides) Polymers 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 230000009261 transgenic effect Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
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- 238000009472 formulation Methods 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
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- 238000010172 mouse model Methods 0.000 description 6
- 238000002600 positron emission tomography Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
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- 102000001049 Amyloid Human genes 0.000 description 5
- 108010094108 Amyloid Proteins 0.000 description 5
- 241000283690 Bos taurus Species 0.000 description 5
- 0 CCCN(CC*)c1ccc(C=C[C@](CC(OC)=N2)N=C2OC)cc1 Chemical compound CCCN(CC*)c1ccc(C=C[C@](CC(OC)=N2)N=C2OC)cc1 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
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- 125000004122 cyclic group Chemical group 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
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- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 5
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- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
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- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0084—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion liposome, i.e. bilayered vesicular structure
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Description
本出願は、2014年10月8日出願の米国仮特許出願第62/061,514号、および2015年2月2日出願の同第62/111,057号の優先権を主張するものであり、その各々は参照により全体が本明細書に組み込まれる。
特定の実施形態を、実施例の形式で以下に記載する。本発明のすべての潜在的な用途を描写することは不可能である。したがって、実施形態は、かなり詳細に記載してあるが、添付の特許請求の範囲をそのような詳細に、もしくは任意の特定の実施形態に制限するか、またはいかなる方法で限定することを意図するものではない。
図1A、1B、および1Cは、化合物i〜xiii、および既知の化合物MeXO4、SB−13およびフロルベタピルを含む様々な化合物のCLogP値および構造を表形式で示す。CLogPは、Log[オクタノール中の濃度/水中の濃度]としての、オクタノール中の化合物の水に対する相対濃度についての分配係数の対数である。より低いCLogP値は、より高い親水性に相当する。MeXO4はアミロイド斑に対する高い親和性を示したが、発明者らはSB−13および臨床に使用されるフロルベタピル中のスチルベン構造が結合における感度および特異性を提供し得ると判断した。発明者らはさらに、ベンゾチアゾールまたはピリミジル部分が既知の化合物と比較してより低いCLogPおよび増加したH結合能を有する類似体を生成し得ると判断した。加えて、ヒドロキシエチル基(複数可)で窒素をキャッピングすると、さらに親水性が増加し、リポソームの脂質二重層中への挿入の代わりに、リポソームの外部の水性媒質中でリガンドが浮遊するのを維持する能力を高めることができた。したがって、i〜xiiiなどの化合物は、ゆえに、スチルベンコアの親水性を増加して二重層を不安定にすることなくリポソーム表面上に提示されるリガンドの能力を増強すると一般的に予想される側鎖修飾を用いて考案した。化合物i〜xiiiはそれぞれ、以前の化合物MeXO4よりも数桁親水性である。理論に束縛されるものではないが、より高い親水性は、例えば、リポソーム外の親水性環境中の、結合に利用可能な構成での対応する化合物の存在を増加させることによって、およびアミロイドβ線維との結合相互作用を増加させることなどによって、アミロイドβ線維との相互作用ならびに結合を促進できると考えられる。
Αβ線維を、全体の教示が参照により本明細書に組み込まれるKlunkら、Ann Neurol,2004;55:306−19の方法に従って合成した。簡潔に述べると、Αβ(1−40)ペプチド(rPeptide,Bogart,GA)を433μg/mL(100μΜ)の最終濃度にpH7.4のリン酸緩衝生理食塩水中に溶解した。この溶液を室温で4時間、700rpmで磁気撹拌棒を用いて撹拌して原線維の形成を促進した。原液を等分し、将来の使用のために−80℃で保存した。原線維の均質な懸濁液を維持するために、結合アッセイ用のアリコートを取り出す前に、ストック溶液を十分に撹拌した。原線維の均質な懸濁液を確実にするために、結合アッセイ用のアリコートを取り出す前にストック溶液を十分に撹拌した。
結合アッセイ:化合物または化合物−標識リポソームのアミロイド線維との結合親和性を、以下の方法によって測定した。競合アッセイ用のリガンド−標識リポソーム、リガンドストック溶液、およびクリサミンGを10mMのTris−HCl、pH7.4で500nMに希釈した。原線維ストック溶液を、200μLの反応混合物中の化合物のストック溶液または化合物標識リポソームと混合し、0.0625〜2.0μΜの試験化合物を有する原線維の最終濃度(20μΜ)を得た。結合混合物を室温で1時間インキュベートした。続いて、インキュベートした結合混合物を16,400rpmで20分間遠心分離して原線維を分離した。原線維沈殿物をTris−HClで2回洗浄した。次いで、蛍光を、それぞれ405nmおよび535nmの励起波長ならびに発光波長を用いて、FilterMax F−5マルチモードプレートリーダー(Molecular devices,Sunnyvale,CA)で測定した。競合結合アッセイは、20μΜの原線維、1.0μΜの試験化合物および様々な量の非蛍光競合物質のクリサミンGを使用し、1時間インキュベートした。
粒径を測定するために、押出プロセスからの定期的な試料および透析濾過後の最終試料をPBSで希釈し、自己相関システムに取り付けられたゴニオメータベースの動的光散乱システム(BI−90,Brookhaven Instruments Corporation,Holtsville,NY)で測定した。532nmの固体レーザーを光源として使用し、90℃で、光電子増倍管で判別検出されるまで調整された試料の濃度から、毎秒約100kカウント(kcps)を得た。相関関数を、相関ビンの指数関数的に離間したセットを使用して測定し、相関関数の初期の指数関数的な降下を捕捉する少なくとも10チャネル、および長期残光を捕捉する10チャネルを確実にした。ダストの特徴である大きな粒径の混入を示す、ベースラインよりも有意に高い長期相関関数を示した相関関数スライスを排除するダスト識別アルゴリズムを用いて、各試料について2分間の相関関数を平均した。得られた平均相関関数を、CONTINアルゴリズムを用いて分析し、体積平均分布を使用して、平均サイズおよび標準偏差を推定した。全ての分布は実質的に単峰性であった(主ピークにおける体積の99%以上)。
脂質二重層の表面上に表面Gdキレートで装飾したリポソームを調製した(ビス−ステアリル鎖がリポソームの二重層中に挿入するようにGdキレートが脂質アンカーBSA−DTPA−Gdにコンジュゲートされる)。図10Aに示すように、これらのリポソームは、低磁場強度で高いGdモル緩和を示した。図10Aにおいて、例示的なリポソームを、より低い磁場強度で遊離Gdキレート(GadobenateDimelglumine、MULTIHANCE(商標)、Bracco Imaging、Monroe Township、NJ)と比較しているが、その差は、遊離キレートが表面提示よりも緩和的である9.4Tでの点まで、より高い磁場強度で徐々に失われる。
化合物iiiのリガンドを使用してアミロイド斑を標的とするデュアルGdリポソームを、したがって、マウス中のアミロイド斑を画像化するそれらの能力について試験した。デュアルGd/化合物iiiリポソームをマウス内に静脈内注射し、1T MRIスキャナーでT1加重スピンエコーシーケンス(TE=32ms、TR=770ms)を用いて4日後にスキャンした。デュアル−Gd/化合物iiiリポソームは、アミロイド保有マウスの2つの異なる系統(15ヶ月齢のTetO/APPswe−indおよび9ヶ月齢のTg2576)において、アミロイド沈着に特徴的なパターンでシグナル増強をもたらした。同じマウスの注射前スキャンおよび同様に注射したアミロイド陰性マウス、ならびに同じ粒子の非標的バージョン(すなわち、化合物iiiを含まない)を注射したアミロイド陽性マウスでは、比較してシグナルは得られなかった。未結合リポソームが循環から除去されるように、4日の遅延を計画した。PEG化リポソームは約24時間の循環半減期を有しており、過去の経験から、4日の遅延が血液プールからのリポソームのほぼ完全な除去に十分であることが示唆された。
リポソームはまた、近赤外イメージングのために、二重層に約0.6モル%のインドシアニングリーン(ICG)を含有していた。図14A〜H4は、死後のマウスの脳の近赤外イメージングの結果を示す。Tg2576マウスの脳切片の共焦点イメージングにより、トランスジェニックマウスの皮質および海馬におけるICGシグナルの増強が明らかになり、非トランスジェニック対照(図14B)と比較した場合APP+脳において局在性がより高い(図14A)ことが示された。高倍率では、図14Eが、図14Aに対応するアミロイド沈着物の特徴的な点状構造を明らかにした;図14Fは、図14Bの対照に相当する。
合成の取り組みは、図1A〜1B中の最低のCLogP値を有する3つの化合物(化合物ii、化合物iおよび化合物iii)に焦点を当てた。合成および精製は効率的であり、全収率は約90%であった。化合物iiおよび化合物iiiを、アミロイド線維の結合および特異性について試験し、非常に類似した結果が得られたことから、アミロイド結合能力は、これらの分子の比較的高い親水性によって顕著に影響されないことが示唆された。実際には、MeXO4で行った類似の研究と比較して本分子はMeXO4よりも非常に強くアミロイド線維に結合するようであり、クリサミン−Gで置換された結合種はMeXO4での80%超と比較して、わずか約60%である。化合物iiiを、そのより低いCLogP値およびわずかにより高いアミロイド結合能力に基づいて、リード候補として選択した。
Claims (15)
- リン脂質−ポリマー−芳香族コンジュゲートを含む膜を含む、リポソーム組成物であって、
前記リン脂質−ポリマー−芳香族コンジュゲート中の芳香族部分が、
によって表され、
前記リン脂質−ポリマー−芳香族コンジュゲート中のリン脂質−ポリマー部分が、
R2は、アルキレンまたはアルコキシアルキレンのうちの1つである1〜6個の炭素原子を含む連結基であり;
R3は、水素、C1−C6アルキル、またはC1−C6アルコキシアルキルであり、且つ、水素以外のR3は、0個、1個または複数の−OHで置換されており;
ピリミジンPは、−OH、−O−アルキルおよび−NH2のうちの0個、1個または複数で置換されており;
nは、約60〜約100の整数であり;
mは、12、13、14、15、16、17、または18のうちの1つである、
リポソーム組成物。 - 前記膜によってカプセル化されたものまたは前記膜に結合したもののうちの少なくとも1つである非放射性磁気共鳴イメージング(MRI)コントラスト増強剤をさらに含む、請求項1に記載のリポソーム組成物。
- 前記膜が、第1のリン脂質および第2のリン脂質をさらに含み、前記第2のリン脂質が、親水性ポリマーで誘導体化されている、請求項1に記載のリポソーム組成物。
- 患者中のアミロイド沈着物の画像化における使用のためのリポソーム組成物であって、
前記リポソーム組成物が、リン脂質−ポリマー−芳香族コンジュゲート(前記リン脂質−ポリマー−芳香族コンジュゲート中の芳香族部分は、
前記使用が、
検出可能な量の前記リポソーム組成物を前記患者中に導入するステップ;
前記リポソーム組成物が1個以上のアミロイド沈着物と結合するのに十分な時間を与えるステップ;および
1個以上のアミロイド沈着物と結合したリポソーム組成物を検出するステップ、
を含む、
リポソーム組成物。 - 前記検出するステップが、磁気共鳴イメージングを用いて検出することを含む、請求項7に記載のリポソーム組成物。
- 前記非放射性磁気共鳴イメージング(MRI)コントラスト増強剤が、前記膜によってカプセル化されており、且つ、前記膜に結合している、請求項7に記載のリポソーム組成物。
- 前記リポソーム組成物が、約100,000、125,000、150,000、165,000、180,000、190,000、および200,000のうちの少なくとも約1つ以上のmM−1s−1の粒子あたりの緩和により特徴付けられる、請求項9に記載のリポソーム組成物。
- 前記使用が、前記1個以上のアミロイド沈着物と結合したリポソーム組成物の検出に応じて前記患者をアルツハイマー病と診断することをさらに含む、請求項7に記載のリポソーム組成物。
- 前記使用が、
前記1個以上のアミロイド沈着物と結合したリポソーム組成物の検出に応じて、アルツハイマー病を潜在的に有するとして前記患者を特定すること;
タウ神経原線維濃縮体の分析に前記患者を供すること;および
前記1個以上のアミロイド沈着物と結合したリポソーム組成物の検出と共にタウ神経原線維濃縮体の存在を決定したら、前記患者をアルツハイマー病と診断すること、
をさらに含む、請求項7に記載のリポソーム組成物。 - 患者中のアミロイド沈着物を画像化するためのキットであって、
リン脂質−ポリマー−芳香族コンジュゲート(前記リン脂質−ポリマー−芳香族コンジュゲート中の芳香族部分は、
説明書であって、
検出可能な量の前記リポソーム組成物を前記患者中へ導入し;
前記リポソーム組成物が1個以上のアミロイド沈着物と結合するのに十分な時間を与え;
1個以上のアミロイド沈着物と結合したリポソーム組成物を検出する
ようにユーザーに指示する説明書、
を含むキット。 - 前記説明書が、1個以上のアミロイド沈着物と結合したリポソーム組成物の検出に応じて前記患者をアルツハイマー病と診断するように前記ユーザーにさらに指示する、請求項14に記載のキット。
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CN107106708A (zh) | 2017-08-29 |
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CN107106708B (zh) | 2021-06-18 |
AU2021203388A1 (en) | 2021-06-24 |
EP3204051B1 (en) | 2019-05-29 |
EP4035688A1 (en) | 2022-08-03 |
AU2015330824A1 (en) | 2017-05-25 |
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EP3204051A1 (en) | 2017-08-16 |
ES2743704T3 (es) | 2020-02-20 |
US20170080111A1 (en) | 2017-03-23 |
MX371295B (es) | 2020-01-24 |
CA2963941A1 (en) | 2016-04-14 |
HK1243335A1 (zh) | 2018-07-13 |
WO2016057812A1 (en) | 2016-04-14 |
US20160101197A1 (en) | 2016-04-14 |
JP2017532378A (ja) | 2017-11-02 |
AU2021203388B2 (en) | 2024-05-30 |
MX2017004695A (es) | 2018-01-24 |
US11141495B2 (en) | 2021-10-12 |
EP3542828A1 (en) | 2019-09-25 |
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